Acute myocardial infarction (AMI) is associated with the induction of a sterile inflammatory response that leads to further injury. The NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a macromolecular structure responsible for the inflammatory response to injury or infection. NLRP3 can sense intracellular danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is primed and triggered by locally released damage-associated molecular patterns and amplifies the inflammatory response and cell death through caspase-1 activation. Here, we examine the scientific evidence supporting a role for NLRP3 in AMI and the available strategies to inhibit the effects of the inflammasome. Our focus is on the beneficial effects seen in experimental models of AMI in preclinical animal models and the initial results of clinical trials.